The actions of melanin-concentrating hormone (MCH) are thought to be involved in anxiety, depression, obesity, and obesity-related disorders. MCH has been found to be a major regulator of eating behaviour and energy homeostasis and is the natural ligand for the 353-amino acid orphan G-protein-coupled-receptor (GPCR) termed SLC-1 (also known as GPR24). SLC-1 is sequentially homologous to the somatostatin receptors, and is frequently referred to as the “melanin-concentrating hormone receptor” (MCH receptor type 1, MCH1 receptor, or MCHR1).
In mice lacking the MCH1 receptor, there is no increased feeding response to MCH, and a lean phenotype is seen, suggesting that this receptor is responsible for mediating the feeding effect of MCH. MCH receptor antagonists have also been shown to block the feeding effects of MCH, and to reduce body weight & adiposity in diet-induced obese mice. The conservation of distribution and sequence of MCH1 receptors suggest a similar role for this receptor in man and rodent species. Hence, MCH1 receptor antagonists have been proposed as a treatment for obesity and other disorders characterised by excessive eating and body weight.
Emerging evidence also suggests that MCHR1 plays a role in the regulation of mood and stress. Within the central nervous system, MCHR1 mRNA and protein are distributed in various hypothalamic nuclei including, for example, the paraventricular nucleus (PVN) and the nucleus accumbens shell; and limbic structures including, for example, the hippocampus, septum, amygdala, locus coeruleus and dorsal raphe nucleus, all of which are thought to be involved in the regulation of emotion and stress.
Introduction of MCH into the medial preoptic area has been reported to induce anxiety, although contrary anxiolytic-like effects of MCH injection have also been reported. Injection of MCH into the nucleus accumbens shell, in which MCHR1 is abundant, decreased mobility in a forced swim test in rats, suggesting a depressive effect. Also, it has been reported that MCHR1 antagonists exhibited antidepressant and anxiolytic-like effects in rodent tests, suggesting a role for MCHR1 in depression and anxiety.
MCH antagonists are thus thought likely to provide benefit to numerous people and to have a potential to alleviate anxiety and depression and be useful for treating obesity and obesity-related conditions.
The histamine H3 receptor is of current interest in developing new medicaments. The H3 receptor is a presynaptic autoreceptor located both in the central and peripheral nervous systems, the skin, and in organs, such as, for example, the lung, the intestine, probably the spleen, and the gastrointestinal tract. Recent evidence suggests the H3 receptor has intrinsic, constitutive activity in vitro as well as in vivo (i.e., it is active in the absence of an agonist). Compounds acting as inverse agonists can inhibit this activity. The histamine H3 receptor has been shown to regulate the release of histamine and also of other neurotransmitters, such as, for example, serotonin and acetylcholine. Some histamine H3 ligands, such as, for example, a histamine H3 receptor antagonist or inverse agonist may increase the release of neurotransmitters in the brain, whereas other histamine H3 ligands, such as, for example, histamine H3 receptor agonists may inhibit the biosynthesis of histamine, as well as, inhibit the release of neurotransmitters. This suggests that histamine H3 receptor agonists, inverse agonists, and antagonists could mediate neuronal activity. As a result, efforts have been undertaken to develop new therapeutics that target the histamine H3 receptor. It is believed that compounds that modulate histamine H3 receptors may be useful in treating cognitive deficiency, in schizophrenia, narcolepsy, obesity, Attention deficit hyperactivity disorder, pain and Alzheimer's disease.